The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometimes has deleterious side effects. A growing demand in pharmaceutical industries is to market a chiral drug in enantiomerically pure form. To meet this challenge, chemists have explored many approaches for acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Among these methods, asymmetric catalysis is often the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. During the last two decades, great effort has been devoted to discovering new asymmetric catalysts and more than a half-dozen commercial industrial processes have used asymmetric catalysis as the key step in the production of enantiomerically pure compounds..sup.1
Asymmetric phosphine ligands have played a significant role in the development of novel transition metal catalyzed asymmetric reactions. Over 1000 chiral diphosphines.sup.2 have been made since the application of the DIPAMP ligand.sup.3 for the industrial production of L-Dopa, yet only a few of these ligands afford the efficiency and selectivity required for commercial applications. Among these ligands, BINAP is one of the most frequently used bidentate chiral phosphines. The axially dissymmetric, fully aromatic BINAP ligand has been demonstrated to be highly effective for many asymmetric reactions. Duphos and related ligands have also shown high enantioselectivities in numerous reactions. However, there are a variety of reactions in which only modest enantioselectivity has been achieved with these ligands. Highly selective chiral ligands are needed to facilitate asymmetric reactions.
FIG. 1 lists known chiral bidentate phosphines (DIPAMT,.sup.3 BPPM,4 DEGPHOS,.sup.5 DIOP,.sup.6 Chiraphos,.sup.7 Skewphos,.sup.8 BINAP,9 Duphos,.sup.10 and BPE.sup.10). While high selectivities were observed in many reactions using some of these chiral diphosphine ligands, there are many reactions where these ligands are not very efficient in terms of activity and selectivity. There are many disadvantages associated with these ligands, which hinder their applications. For DIPAMP, the phosphine chiral center is difficult to make. This ligand is only useful for asymmetric hydrogenation reaction. For BPPM, DIOP and Skewphos, the methylene group in the ligands causes conformational flexibility and enantioselectivities are moderate for many catalytic asymmetric reaction. DEGPHOS and CHIRAPHOS coordinate transition metal in five-membered ring. The chiral environment created by the phenyl groups is not close to the substrates and enantioselectivities are moderate. BINAP, DuPhos and BPE ligands are good for many asymmetric reactions. However, the rotation of aryl--aryl bond makes BINAP very flexible. The flexibility is an inherent limitation in the use of phosphine ligands. Furthermore, because the BINAP contains three aryl groups, it is less electron donating than phosphines that have less aryl groups. This is an important factor which influences reaction rates. For hydrogenation reactions, electron donating phosphines are more active. For the more electron donating DUPHOS and PBE ligands, the five membered ring adjacent to the phosphines is flexible.
U.S. Pat. Nos. 5,329,015; 5,386,061; 5,532,395 describe phosphines prepared through chiral 1,4-diols. These patents also describe divalent aryl and ferrocene bridging groups. U.S. Pat. No. 5,258,553 describes chiral tridentate ligand phosphine ligands. The above ligands are made into Group VIII transitional catalyst and are used to conduct enantioselective catalytic reactions such as asymmetric hydrogenation of olefins, ketones and imines. These references illustrate the preparation of catalyst from phosphine ligands and the conducting of various asymmetric synthesis. These patent disclosures are incorporated herein by reference.
The present invention discloses several new bidentate and monodentate phosphine ligands for asymmetric catalysis. The common feature of these ligands are that they contain rigid ring structures useful for restricting conformational flexibility of the ligands, thus enhancing chiral recognition. The present invention provides families of chiral diphosphines by variation of the steric and electronic environments (i.e., change of P-M-P bite angles and substituents on phosphine). In such a manner, the present invention provides an efficient and economical method with which to synthesize chiral drugs and agrochemicals.